Comprehensive Study about Verification of GMP Compliance at API Manufacturers published by DMA

On 20 May 2010 the Danish Medicines Agency (DMA) published results of a survey to examine the extent to which manufactureres of medicinal products comply with their obligation to ensure that APIs used in the manufacture of medicinal products comply with the GMP regulations. The manufacturer of medicinal products is obliged to use only those APIs that have been manufactured according to ICH Q7 (identical to Part 2 of the EU GMP Guide). The following information is taken from the DMA report:

In total, documentation for 77 medicinal products and related APIs was received from MAHs. In its review of the API documentation, the Agency identified different types of errors. The errors were divided into three categories:


(a) Audit frequency: Controls in which API manufacturers were audited at a lower frequency than recommended.

In 10% of the controls, it had been more than three years since the last audit of the API manufacturer by the finished product manufacturer. In 1% of the controls, the finished product manufacturer had never audited the API manufacturer; the Agency considers this a serious error.

(b) Certificates of analysis: Controls with errors or defects in certificates of analysis.

In 29% of the controls, the Agency observed errors and defects in respect of the certificates of analysis, e.g.: missing signature or dating, missing re-test date, or re-test interval that differs from the DMF or the CEP, results listed as 'conforms' even though it is possible to specify a numerical result. In 4% of the controls, the Agency observed acceptance limits for assay or related substances that were wider than stated in the specification. This is considered a serious error. No results in the certificates of analysis submitted deviated from the specifications submitted.

(c) Reduced testing of APIs (Controls in which reduced testing was used of APIs at the finished product manufacturer without this having been approved)

The most frequent or significant observations made by medicines inspectors and the Agency's laboratory have been compared and are discussed below:

- Inadequate audit reports from audits of API manufacturers

In connection with the project, it was observed that audit reports requested from Danish finished product manufacturers were inadequate. An audit conducted before qualification of a new API manufacturer should cover all relevant processes related to the manufacture and handling of the API used. In subsequent audits of the API manufacturer, it is natural not to focus on the same areas as those focused on in the previous audit. An audit report is thus not expected to describe all processes relevant to the API in question. Auditors should instead focus on areas that have not been audited recently or that have previously proved a challenge for the API manufacturer.

- Inadequate or no follow-up on deficiencies found during audits of API manufacturers

In their review of audit reports, the medicines inspectors observed that it took up to a year to provide a reply to and close deficiencies after the latest audit, and, in some cases, they observed that deficiencies found more than a year ago still had not been handled.

In an audit carried out before qualification of a new API manufacturer, all deficiencies should be closed before APIs from the API manufacturer in question are used. Similarly, the finished product manufacturer should, based on a risk assessment, decide whether he will continue using an already qualified API manufacturer if the API manufacturer is unable to provide a satisfactory reply to deficiencies.

- Missing documentation for the auditor's qualifications and independence

During inspections of finished product manufacturers, medicines inspectors observed that neither CVs for auditors nor documentation for training could be produced.

When requesting third-party audit reports, finished product manufacturers must, in particular, focus on the auditors being sufficiently qualified and independent of the audited API manufacturers. Special caution should be exercised when using auditors affiliated with traders or finished product manufacturers supplying APIs, intermediate products or finished products to other companies.

The following further deviations have been identified:

- Missing approval of audit reports from the qualified person with the finished product manufacturer
- Missing audit of all relevant suppliers (not all relevant traders had been audited)
- Lower frequency of audits of API manufacturers than recommended (Audits should, as a minimum, be carried out every three years.)
- Audit reports not comparable with medicines inspectors' observations
- Lack of action from MAHs on withdrawn CEP
- Reduced testing of APIs (Such use of reduced testing must be authorised by the Danish Medicines Agency and be described in the marketing authorisation, cf. section 26(1) of the Danish Medicines Act.)
- Use of monograph and in-house methods (If a company experiences that Ph. Eur. monographs do not work as intended, this should be communicated to the EDQM or the Danish Medicines Agency.)
- The registration department and the QC department do not work with synchronised specifications (In approx. 10% of the controls, the specifications from the MAH's registration department differed from those in the finished product manufacturer's QC department.)
- Uncertainty about reference samples (In connection with the request for APIs, some companies were not able to deliver the requested quantity to the Agency.)

The DMA plans to develop and publish further guidelines for the development of audit reports and will provide advice on the role of the QP with regard to API compliance in connection with the release of medicinal products.

Source: Danish Medicines Agency 

Tip: APIC/CEFIC offers a comprehensive Third Party Auditing Programme. Companies like Genzyme, Pfizer and Boehringer Ingelheim already participated in this Audit Scheme. To become an APIC certified auditor you can take advantage of the qualification programme offered jointly with ECA. You will find more about the Audit Scheme here:

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